Guidance for Reviewers Pharmacology/Toxicology Review Format

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Pharmacology/Toxicology

May 2001 Guidance for Reviewers Pharmacology/Toxicology Review Format

Additional copies are available from:

Drug Information Branch (HFD-210) Center for Drug Evaluation and Research (CDER) 5600 Fishers Lane, Rockville, MD 20857, (Tel) 301-827-4570 Internet at http://www.fda.gov/der/guidance/index.htm

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Pharmacology/Toxicology

May 2001 Guidance for Reviewers Table of Contents

I. INTRODUCTION ...... 1

II. BACKGROUND...... 1

III. DISCUSSION ...... 1

A. IND REVIEW FORMAT ...... 1

B. NDA REVIEW FORMAT...... 1

IV. ATTACHMENTS ...... 1

A. IND REVIEW FORMAT ...... A-i

B. NDA REVIEW FORMAT...... B-i Guidance for Reviewers1

Pharmacology/Toxicology Review Format

I. INTRODUCTION

This document contains as attachments internal FDA review formats currently being used by pharmacology/toxicology reviewers in IND and NDA primary reviews. The attached format documents are being published to provide internal and external stakeholders with an understanding of the standard format and content of pharmacology/toxicology reviews. FDA uses the format documents for a number of reasons. First of all, standardization provides for unified communication amongst multiple audiences, including secondary reviewers, re-assigned reviewers, and ultimately the American public. Standardization also ensures that the most important information is captured in all reviews. In addition, the standard format makes it readily apparent what types of studies have and have not been reviewed, and assists other reviewers when reviews are referenced at later times. Reviewers use these formats for most original, supplemental, and amended applications. In some cases the formats may not be used, such as for safety studies or consults to other groups, where short response times restrict their use. These format documents are consistent with the ICH Common Technical Document (CTD) and will eventually be considered in the Center-wide Good Review Practices (GRP) initiative.

II. DISCUSSION

A. IND Review Format

For IND reviews, the reviewer should use only the headers for which there is data. Thus, in the majority of IND reviews, many of the headers will not be used.

B. NDA Review Format

For NDA reviews, the reviewer should use all the headers, including those for which there are no data. If there are no data, a note will be made that data were not submitted. Thus, for NDA reviews, all of the headers will be listed, with a brief note following the headers for which there are no data.

1 This guidance has been prepared by the Associate Director for Pharmacology and Toxicology, Office of Review Management in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA). This guidance document represents the Agency’s current format used for pharmacology/toxicology reviews. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both. 1 III. ATTACHMENTS

A. IND Review Format B. NDA Review Format

2 ATTACHMENT A: IND REVIEW FORMAT PHARMACOLOGY/TOXICOLOGY

IND number: Review number: Sequence number/date/type of submission: Information to sponsor: Yes ( ) No ( ) Sponsor and/or agent: Manufacturer for drug substance :

Reviewer name: Division name: HFD #: Review completion date:

Drug: Trade name: Generic name (list alphabetically): Code name: Chemical name: CAS registry number: Mole file number: Molecular formula/molecular weight: Structure:

Relevant INDs/NDAs/DMFs:

Drug class:

Indication:

Clinical formulation:

Route of administration:

Proposed clinical protocol:

Previous clinical experience:

Disclaimer: Tabular and graphical information is from sponsor’s submission unless stated otherwise.

A-i OVERALL SUMMARY AND EVALUATION:

Introduction:

Safety evaluation:

Safety issues relevant to clinical use:

Other clinically relevant issues:

Conclusions:

Communication review: Investigator’s brochure/informed consent review:

RECOMMENDATIONS:

Internal comments:

External recommendations (to sponsor):

Draft letter content for sponsor (if not same as above):

Future development issues:

Reviewer signature:

Team leader signature [concurrence/non-concurrence]: cc: list:

Memorandum of non-concurrence (if appropriate, attached):

Addendum to review (if necessary):

A-ii Studies reviewed within this submission:

Studies not reviewed within this submission:

Introduction and drug history:

A-iii TABLE OF CONTENTS

PHARMACOLOGY:...... A-1 SAFETY PHARMACOLOGY:...... A-1 PHARMACOKINETICS/TOXICOKINETICS:...... A-2 TOXICOLOGY:...... A-3 Histopathology Inventory for IND # ...... A-4 GENETIC TOXICOLOGY:...... A-7 CARCINOGENICITY:...... A-9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY:...... A-11 SPECIAL TOXICOLOGY STUDIES:...... A-13 APPENDIX/ATTACHMENTS:...... A-14

A-iv Reviewer: IND No.

PHARMACOLOGY:

Primary pharmacodynamics: Mechanism of action:

Drug activity related to proposed indication:

Secondary pharmacodynamics:

Pharmacology summary:

Pharmacology conclusions:

SAFETY PHARMACOLOGY:

Neurological effects:

Cardiovascular effects:

Pulmonary effects:

Renal effects:

Gastrointestinal effects:

Abuse liability:

Other:

Safety pharmacology summary:

Safety pharmacology conclusions:

A-1 Reviewer: IND No.

PHARMACOKINETICS/TOXICOKINETICS:

PK parameters:

Absorption:

Distribution:

Metabolism:

Excretion:

Other studies:

PK/TK summary:

PK/TK conclusions:

A-2 Reviewer: IND No.

TOXICOLOGY:

Study title:

Key study findings:

Study no: Volume #, and page #: Conducting laboratory and location: Date of study initiation: GLP compliance: QA report: yes ( ) no ( ) Drug, lot #, radiolabel, and % purity: Formulation/vehicle:

Methods (unique aspects): Dosing: Species/strain: #/sex/group or time point (main study): Satellite groups used for toxicokinetics or recovery: Age: Weight: Doses in administered units: Route, form, volume, and infusion rate:

Observations and times: Clinical signs: Body weights: Food consumption: Ophthalmoscopy: EKG: Hematology: Clinical chemistry: Urinalysis: Gross pathology: Organs weighed: Histopathology: Toxicokinetics: Other:

Results: Mortality: Clinical signs: Body weights: A-3 Reviewer: IND No.

Food consumption: Ophthalmoscopy: Electrocardiography: Hematology: Clinical chemistry: Urinalysis: Organ weights: Gross pathology: Histopathology: Toxicokinetics:

Summary of individual study findings:

Toxicology summary:

Toxicology conclusions:

Histopathology Inventory for IND #

Study Species Adrenals Aorta Bone Marrow smear Bone (femur) Brain Cecum Cervix Colon Duodenum Epididymis Esophagus Eye Fallopian tube Gall bladder Gross lesions Harderian gland Heart Ileum Injection site Jejunum A-4 Reviewer: IND No.

Kidneys Lachrymal gland Larynx Liver Lungs Lymph nodes, cervical Lymph nodes mandibular Lymph nodes, mesenteric Mammary Gland Nasal cavity Optic nerves Ovaries Pancreas Parathyroid Peripheral nerve Pharynx Pituitary Prostate Rectum Salivary gland Sciatic nerve Seminal vesicles Skeletal muscle Skin Spinal cord Spleen Sternum Stomach Testes Thymus Thyroid Tongue Trachea Urinary bladder Uterus Vagina Zymbal gland Standard List

A-5 Reviewer: IND No.

X, histopathology performed *, organ weight obtained

A-6 Reviewer: IND No.

GENETIC TOXICOLOGY:

Study title:

Key findings:

Study no: Study type (if not reflected in title): Volume #, and page #: Conducting laboratory and location: Date of study initiation: GLP compliance: QA reports: yes ( ) no ( ) Drug, lot #, radiolabel, and % purity: Formulation/vehicle:

Methods: Strains/species/cell line: Dose selection criteria: Basis of dose selection: Range finding studies: Test agent stability: Metabolic activation system: Controls: Vehicle: Negative controls: Positive controls: Comments: Exposure conditions: Incubation and sampling times: Doses used in definitive study: Study design: Analysis: No. of replicates: Counting method: Criteria for positive results:

Summary of individual study findings: Study validity: Study outcome:

Genetic toxicology summary:

Genetic toxicology conclusions: A-7 Reviewer: IND No.

Labeling recommendations:

A-8 Reviewer: IND No.

CARCINOGENICITY:

Study title:

Key study findings:

Study number: Volume #, and page #: Conducting laboratory and location: Date of study initiation: GLP compliance: QA report: yes ( ) no ( ) Drug, lot #, and % purity: CAC concurrence:

Study Type (2 yr bioassay, alternative model etc.): Species/strain: Number/sex/group; age at start of study: Animal housing: Formulation/vehicle: Drug stability/homogeneity: Methods: Doses: Basis of dose selection: Restriction paradigm for dietary restriction studies: Route of administration: Frequency of drug administration: Dual controls employed: Interim sacrifices: Satellite PK or special study group(s): Deviations from original study protocol: Statistical methods:

Observations and times: Clinical signs: Body weights: Food consumption: Hematology: Clinical chemistry: Organ weights: Gross pathology: Histopathology: Toxicokinetics:

A-9 Reviewer: IND No.

Results: Mortality: Clinical signs: Body weights: Food consumption: Hematology: Clinical chemistry: Organ weights: Gross pathology: Histopathology: Non-neoplastic: Neoplastic: Toxicokinetics:

Summary of individual study findings: Adequacy of the carcinogenicity study and appropriateness of the test model: Evaluation of tumor findings:

Carcinogenicity summary:

Carcinogenicity conclusions: Recommendations for further analysis:

Labeling Recommendations:

Addendum/appendix listing: Dose-ranging study report: CAC report: Alternative study protocols and CAC report: Sponsor’s incidence of histopathology findings: List of organs and tissues examined: Body weight changes versus dose level: Group body weight summary: Individual data listing:

A-10 Reviewer: IND No.

REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY:

Study title:

Key study findings:

Study no.: Volume #, and page #: Conducting laboratory and location: Date of study initiation: GLP compliance: QA reports: yes ( ) no ( ) Drug, lot #, radiolabel, and % purity: Formulation/vehicle:

Methods: Species/strain: Doses employed: Route of administration: Study design: Number/sex/group: Parameters and endpoints evaluated:

Results: Mortality: Clinical signs: Body weight: Food consumption: Toxicokinetics:

For fertility studies: In-life observations: Terminal and necroscopic evaluations:

For embyrofetal development studies: In-life observations: Terminal and necroscopic evaluations: Dams: Offspring:

OR A-11 Reviewer: IND No.

For peri-postnatal development studies: In-life observations: Dams: Offspring:

Terminal and necroscopic evaluations: Dams: Offspring:

Summary of individual study findings:

Reproductive and developmental toxicology summary:

Reproductive and developmental toxicology conclusions:

Labeling recommendations:

A-12 Reviewer: IND No.

SPECIAL TOXICOLOGY STUDIES:

Study title:

Key study findings:

Study no: Volume #, and page #: Conducting laboratory and location: Date of study initiation: GLP compliance: QA reports: yes ( ) no ( ): Drug, lot #, radiolabel, and % purity: Formulation/vehicle:

Methods: Dosing:

Observations and times:

Results:

Summary of individual study findings:

Conclusions:

A-13 Reviewer: IND No.

ADDENDUM TO REVIEW: (if necessary)

APPENDIX/ATTACHMENTS:

A-14 ATTACHMENT B: NDA REVIEW FORMAT PHARMACOLOGY/TOXICOLOGY

NDA number: Review number: Serial number/date/type of submission: Information to sponsor: Yes ( ) No ( ) Sponsor and/or agent: Manufacturer for drug substance :

Reviewer name: Division name: HFD #: Review completion date:

Drug: Trade name: Generic name (list alphabetically): Code name: Chemical name: CAS registry number: Mole file number: Molecular formula/molecular weight: Structure:

Relevant INDs/NDAs/DMFs:

Drug class:

Indication:

Clinical formulation:

Route of administration:

Proposed use:

Disclaimer: Tabular and graphical information is from sponsor’s submission unless stated otherwise.

B-i OVERALL SUMMARY AND EVALUATION:

Introduction:

Safety evaluation:

Safety issues relevant to clinical use:

Other clinically relevant issues:

Conclusions:

Communication review: Labeling review:

RECOMMENDATIONS:

Internal comments:

External recommendations (to sponsor):

Draft letter content for sponsor (if not same as above):

NDA issues:

Reviewer signature:

Team leader signature [concurrence/non-concurrence]: cc: list:

Memorandum of non-concurrence (if appropriate, attached):

Addendum to review (if necessary):

B-ii Studies reviewed within this submission:

Studies not reviewed within this submission:

Introduction and drug history:

B-iii TABLE OF CONTENTS

PHARMACOLOGY:...... B-1 SAFETY PHARMACOLOGY:...... B-1 PHARMACOKINETICS/TOXICOKINETICS:...... B-2 TOXICOLOGY:...... B-3 Histopathology Inventory for NDA #...... B-4 GENETIC TOXICOLOGY:...... B-7 CARCINOGENICITY:...... B-8 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY:...... B-10 SPECIAL TOXICOLOGY STUDIES:...... B-12 ADDENDUM TO REVIEW:...... B-13 APPENDIX/ATTACHMENTS:...... B-13

B-iv Reviewer: NDA No.

PHARMACOLOGY:

Primary pharmacodynamics: Mechanism of action:

Drug activity related to proposed indication:

Secondary pharmacodynamics:

Pharmacology summary:

Pharmacology conclusions:

SAFETY PHARMACOLOGY:

Neurological effects:

Cardiovascular effects:

Pulmonary effects:

Renal effects:

Gastrointestinal effects:

Abuse liability:

Other:

Safety pharmacology summary:

Safety pharmacology conclusions:

B-1 Reviewer: NDA No.

PHARMACOKINETICS/TOXICOKINETICS:

PK parameters:

Absorption:

Distribution:

Metabolism:

Excretion:

Other studies:

PK/TK summary:

PK/TK conclusions:

B-2 Reviewer: NDA No.

TOXICOLOGY:

Study title:

Key study findings:

Study no: Volume #, and page #: Conducting laboratory and location: Date of study initiation: GLP compliance: QA report: yes ( ) no ( ) Drug, lot #, radiolabel, and % purity: Formulation/vehicle:

Results: Mortality: Clinical signs: Body weights: B-3 Reviewer: NDA No.

Food consumption: Ophthalmoscopy: Electrocardiography: Hematology: Clinical chemistry: Urinalysis: Organ weights: Gross pathology: Histopathology: Toxicokinetics:

Summary of individual study findings:

Toxicology summary:

Toxicology conclusions:

Histopathology Inventory for NDA #

Lachrymal gland Larynx Liver Lungs Lymph nodes, cervical Lymph nodes mandibular Lymph nodes, mesenteric Mammary Gland Nasal cavity Optic nerves Ovaries Pancreas Parathyroid Peripheral nerve Pharynx Pituitary Prostate Rectum Salivary gland Sciatic nerve Seminal vesicles Skeletal muscle Skin Spinal cord Spleen Sternum Stomach Testes Thymus Thyroid Tongue Trachea Urinary bladder Uterus Vagina Zymbal gland Standard List

X, histopathology performed

B-5 Reviewer: NDA No.

*, organ weight obtained

B-6 Reviewer: NDA No.

GENETIC TOXICOLOGY:

Study title:

Key findings:

Summary of individual study findings: Study validity: Study outcome:

Genetic toxicology summary:

Genetic toxicology conclusions: B-7 Reviewer: NDA No.

Labeling recommendations:

CARCINOGENICITY:

Study title:

Key study findings:

Study number: Volume #, and page #: Conducting laboratory and location: Date of study initiation: GLP compliance: QA report: yes ( ) no ( ) Drug, lot #, and % purity: CAC concurrence:

Observations and times: Clinical signs: Body weights: Food consumption: Hematology: Clinical chemistry: Organ weights: Gross pathology: B-8 Reviewer: NDA No.

Histopathology: Toxicokinetics:

Results: Mortality: Clinical signs: Body weights: Food consumption: Hematology: Clinical chemistry: Organ weights: Gross pathology: Histopathology: Non-neoplastic: Neoplastic: Toxicokinetics:

Summary of individual study findings: Adequacy of the carcinogenicity study and appropriateness of the test model: Evaluation of tumor findings:

Carcinogenicity summary:

Carcinogenicity conclusions: Recommendations for further analysis:

Labeling Recommendations:

B-9 Reviewer: NDA No.

REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY:

Study title:

Key study findings:

Study no.: Volume #, and page #: Conducting laboratory and location: Date of study initiation: GLP compliance: QA reports: yes ( ) no ( ) Drug, lot #, radiolabel, and % purity: Formulation/vehicle:

Methods: Species/strain: Doses employed: Route of administration: Study design: Number/sex/group: Parameters and endpoints evaluated:

Results: Mortality: Clinical signs: Body weight: Food consumption: Toxicokinetics:

For fertility studies: In-life observations: Terminal and necroscopic evaluations:

For embyrofetal development studies: In-life observations: Terminal and necroscopic evaluations: Dams: Offspring:

OR B-10 Reviewer: NDA No.

For peri-postnatal development studies: In-life observations: Dams: Offspring:

Terminal and necroscopic evaluations: Dams: Offspring:

Summary of individual study findings:

Reproductive and developmental toxicology summary:

Reproductive and developmental toxicology conclusions:

Labeling recommendations:

B-11 Reviewer: NDA No.

SPECIAL TOXICOLOGY STUDIES:

Study title:

Key study findings:

Study no: Volume #, and page #: Conducting laboratory and location: Date of study initiation: GLP compliance: QA reports: yes ( ) no ( ): Drug, lot #, radiolabel, and % purity: Formulation/vehicle:

Methods: Dosing:

Observations and times:

Results:

Summary of individual study findings:

Conclusions:

B-12 Reviewer: NDA No.

ADDENDUM TO REVIEW: (if necessary)

APPENDIX/ATTACHMENTS:

B-13